Investigating the Effects of Indirect Coculture of Human Mesenchymal Stem Cells on the Migration of Breast Cancer Cells: A Systematic Review and Meta-Analysis.

Purpose: Breast cancer is the most diagnosed cancer and the leading cause of cancer death in women globally, and mesenchymal stem cells have been widely implicated in tumour progression. This systematic review and meta-analysis seeks to identify and summarise existing literature on the effects of human mesenchymal stem cells (hMSCs) on the migration of breast cancer cells (BCCs) in vitro, to determine the direction of this relationship according to existing research and to identify the directions for future research. Methods: A systematic literature search was conducting using a collection of databases, using the following search terms: in vitro AND mesenchymal stem cells AND breast cancer. Only studies that investigated the effects of human, unmodified MSCs on the migration of human, unmodified BCCs in vitro were included. Standardised mean differences (SMDs) were calculated to determine pooled effect sizes. Results: This meta-analysis demonstrates that hMSCs (different sources combined) increase the migration of both MDA-MB-231 and MCF-7 cell lines in vitro (SMD = 1.84, P = .03 and SMD = 2.69, P < .00001, respectively). Importantly, the individual effects of hMSCs from different sources were also analysed and demonstrated that MSCs derived from human adipose tissue increase BCC migration (SMD = 1.34, P = .0002) and those derived from umbilical cord increased both MDA-MB-231 and MCF-7 migration (SMD = 3.93, P < .00001 and SMD = 3.01, P < .00001, respectively). Conclusions: To our knowledge, this is the first systematic review and meta-analysis investigating and summarising the effects of hMSCs from different sources on the migration of BCCs, in vitro.

Cryopreservation of Human Bone Marrow Derived Mesenchymal Stem Cells at High Concentration Is Feasible.

Introduction: For stem cell therapies to be adopted in mainstream health care, robust, reliable, and cost-effective storage and transport processes must be developed. Cryopreservation remains the best current platform for this purpose, and freezing cells at high concentration may have many benefits, including savings on cost and storage space, facilitating transport logistics, and reducing cryoprotectant volume. Cells, such as mesenchymal stem cells (MSCs), are typically frozen at 1 million cells per milliliter (mL), but the aim of this study is to examine the post-thaw attributes of human bone marrow derived MSCs (hBM-MSCs) frozen at 1, 5, and 10 million cells per mL. Methods: Thawed cells were assessed for their morphology, phenotypic marker expression, viability, apoptosis level, metabolic activity, proliferation, and osteogenic and adipogenic differentiation. Results: In this study, for the first time, it is shown that all assessed cells expressed the typical MSC markers (CD90, CD105, and CD73) and lacked the expression of CD14, CD20, CD34, CD45, and HLA-DR. In addition, all cells showed elongated fibroblastic morphology. Post-thaw viability was retained with no difference among the three concentrations. Moreover, no significant statistical difference was observed in the post-thaw apoptosis level, metabolic activity, proliferation, and osteogenic potential, indicating that these cells are amenable to cryopreservation at higher concentrations. Conclusion: The results of this study are of paramount importance to the development of manufacturing processes around a useful freezing concentration when cells are targeted to be stored for at least 6 months.

The lasting effects of resistance and endurance exercise interventions on breast cancer patient mental wellbeing and physical fitness.

Breast cancer is a persisting global burden for health services with cases and deaths projected to rise in future years. Surgery complemented by adjuvant therapy is commonly used to treat breast cancer, however comes with detrimental side effects to physical fitness and mental wellbeing. The aim of this systematic review and meta-analysis is to determine whether resistance and endurance interventions performed during adjuvant treatment can lastingly ameliorate these side effects. A systematic literature search was performed in various electronic databases. Papers were assessed for bias and grouped based on intervention design. RStudio was used to perform the meta-analyses for each group using the 'meta' package. Publication bias and power analyses were also conducted. These methods conform to PRISMA guidelines. Combined resistance and endurance interventions elicited significant long-lasting improvements in global fatigue and were beneficial to the remaining side effects. Individually, resistance and endurance interventions non-significantly improved these side effects. Resistance interventions elicited higher benefits overall. Exercise interventions have lasting clinical benefits in ameliorating adjuvant therapy side effects, which negatively impact physical fitness and mental wellbeing. These interventions are of clinical value to enhance adherence rates and avoid comorbidities such as sarcopenia, thus improving disease prognosis.

The Productivity Requirements of Implementing a Medical Scribe Program.

BACKGROUND: Economic analyses of medical scribes have been limited to individual, specialty-specific clinics. OBJECTIVE: To determine the number of additional patient visits various specialties would need to recover the costs of implementing scribes in their practice at 1 year. DESIGN: Modeling study based on 2015 data from the Centers for Medicare & Medicaid Services (CMS) and National Ambulatory Medical Care Survey. Scribe costs were based on literature review and a third-party contractor model. Revenue was calculated from direct visit billing, CPT (Current Procedural Terminology) billing, and data from the National Ambulatory Medical Care Survey. DATA SOURCES: 2015 data from CMS and the National Ambulatory Medical Care Survey. TARGET POPULATION: Health care providers. TIME HORIZON: 1 year. PERSPECTIVE: Office-based clinic. OUTCOME MEASURES: The number of additional patient visits a physician must have to recover the costs of a scribe program at 1 year. RESULTS OF BASE-CASE ANALYSIS: An average of 1.34 additional new patient visits per day (295 per year) were required to recover scribe costs (range, 0.89 [cardiology] to 1.80 [orthopedic surgery] new patient visits per day). For returning patients, an average of 2.15 additional visits per day (472 per year) were required (range, 1.65 [cardiology] to 2.78 [orthopedic surgery] returning visits per day). The addition of 2 new patient (or 3 returning) visits per day was profitable for all specialties. RESULTS OF SENSITIVITY ANALYSIS: Results were not sensitive to most inputs, with the exception of hourly scribe cost and inclusion of CPT revenue. LIMITATION: Use of Medicare data and failure to account for indirect costs, downstream revenue, or changes in documentation quality. CONCLUSION: For all specialties, modest increases in productivity due to scribes may allow physicians to see more patients and offset scribe costs, making scribe programs revenue-neutral. PRIMARY FUNDING SOURCE: University of Chicago Medicine's Center for Healthcare Delivery Science and Innovation and the Bucksbaum Institute.

An exploration of the role of exercise in modulating breast cancer progression in vitro: a systematic review and meta-analysis.

Breast cancer is the most prevalent cancer in women worldwide. In the United Kingdom, approximately 5% of all breast cancers are already metastatic at the time of diagnosis. An abundance of literature shows that exercise can have beneficial effects on the outcome and prognosis of breast cancer patients, yet the molecular mechanisms remain poorly understood. There are several in vitro models that aim to recapitulate the response of breast cancer to exercise in vivo; this systematic review and meta-analysis summarizes the existing literature. The following search terms were used to conduct a systematic literature search using a collection of databases (last search performed May 2020): "in vitro," "exercise," and "breast cancer." Only studies that investigated the effects of exercise on breast cancer in vitro were included. Standardized mean differences (SMD) were calculated to determine pooled effect sizes. This meta-analysis has successfully demonstrated that various identified exercise interventions on breast cancer cells in vitro significantly reduced breast cancer cell viability, proliferation, and tumorigenic potential (SMD = -1.76, P = 0.004, SMD = -2.85, P = 0.003, and SMD = -3.15, P = 0.0008, respectively). A clear direction of effect was found with exercise on breast cancer cell migration in vitro, however this effect was not significant (SMD = -0.62, P = 0.317). To our knowledge, this is the first meta-analysis and systematic review investigating and summarizing literature on exercise and breast cancer in vitro, highlighting models used and priority areas for future research focus.

A Call to Action: Ethics Committee Roundtable Recommendations for Addressing Burnout and Moral Distress in Oncology.

Oncologist well-being is critical to initiating and maintaining the physician-patient relationship, yet many oncologists suffer from symptoms of burnout. Burnout has been linked to poor physical and mental health, as well as increased medical errors, patient dissatisfaction, and workforce attrition. In this Call to Action article, we discuss causes of and interventions for burnout and moral distress in oncology, highlight existing interventions, and provide recommendations for addressing burnout and improving well-being at the individual and organizational levels to deliver ethical, quality cancer care.

Determining Conditions for Successful Culture of Multi-Cellular 3D Tumour Spheroids to Investigate the Effect of Mesenchymal Stem Cells on Breast Cancer Cell Invasiveness.

Mesenchymal stem cells have been widely implicated in tumour development and metastases. Moving from the use of two-dimensional (2D) models to three-dimensional (3D) to investigate this relationship is critical to facilitate more applicable and relevant research on the tumour microenvironment. We investigated the effects of altering glucose concentration and the source of foetal bovine serum (FBS) on the growth of two breast cancer cell lines (T47D and MDA-MB-231) and human bone marrow-derived mesenchymal stem cells (hBM-MSCs) to determine successful conditions to enable their co-culture in 3D tumour spheroid models. Subsequently, these 3D multi-cellular tumour spheroids were used to investigate the effect of hBM-MSCs on breast cancer cell invasiveness. Findings presented herein show that serum source had a statistically significant effect on two thirds of the growth parameters measured across all three cell lines, whereas glucose only had a statistically significant effect on 6%. It was determined that the optimum growth media composition for the co-culture of 3D hBM-MSCs and breast cancer cell line spheroids was 1 g/L glucose DMEM supplemented with 10% FBS from source A. Subsequent results demonstrated that co-culture of hBM-MSCs and MDA-MB-231 cells dramatically reduced invasiveness of both cell lines (F(1,4) = 71.465, p = 0.001) when embedded into a matrix comprising of growth-factor reduced base membrane extract (BME) and collagen.

Adherence to anti-estrogen therapy in women with hormone receptor-positive breast cancer utilizing bubble packaging: a pilot study.

PURPOSE: This pilot study evaluated adherence to anti-estrogen therapy in women with hormone receptor-positive breast cancer utilizing bubble packaging. METHODS: This was a single-arm prospective investigational pilot study that enrolled 86 patients between August 2012 and April 2014. Descriptive statistics for patient age, race, insurance, stage, duration of treatment, and comorbidities were computed. All patients received routine prescriptions in a "bubble" pack or daily blister pack dispensed by one pharmacy. Participants were considered adherent if they had taken ≥ 80% of the dispensed drug. Disease-free survival (DFS) and overall survival (OS) data were obtained at 78 months. RESULTS: Fifty patients were included in the analysis. The overall adherence rate was 97%. None of the variables examined (race, age, insurance status, and stage) had an impact on adherence rate. Only duration of endocrine therapy had a marginal effect on adherence (p value = 0.06). The late cohort (duration of therapy 37-60 months) was least likely to be compliant at 89.53%. Our 5-year DFS was 94% and 5-year OS was 96%. There was no statistically significant difference in DFS and OS between patients with adherence rate > 90% and < 90%. CONCLUSION: Adherence rate to bubble packaging was higher than that in historical studies. Although this is a single-arm pilot study, these data suggest bubble packaging of anti-estrogen may be a reasonable option to improve adherence in hormone receptor-positive breast cancer patients.

Screening for Posttraumatic Stress Disorder in Civilians With Mangled Hand Injury: A Practice Enhancement Approach.

Posttraumatic stress disorder (PTSD) is a symptom cluster of intrusion, avoidance, negative alteration in cognition, and alteration in arousal and reactivity following trauma. PTSD occurs frequently after a physical trauma such as a severe hand injury. It is often not recognized and consequently untreated. Previous research has shown that 10%-40% of civilian trauma survivors experience PTSD in the first 12 months after injury. There is great urgency to identify patients in the early stage of recovery from trauma, as PTSD becomes more difficult to treat in its chronic form. Mangling hand injuries are particularly disabling because they are an integral part of our social body image. We wanted to investigate the degree of PTSD screening and the follow-up-referral procedures in all mangled hand cases at the hand clinic of a large Northwestern Trauma Center. A retrospective medical record review was conducted from January to December 2012 using an existing PTSD screen with data from the electronic medical records. We found that 40% of the patients with mangled hand injury were classified as "at risk" according to our PTSD screening but only 22% of those cases were referred to rehabilitation psychiatry for further evaluation and treatment. The low rate of referral for PTSD after mangled hand injury was alarming. On the basis of this, we instituted a new screening protocol for all patients with mangled hand injury using the 4-item Primary Care-PTSD screening tool and provided an informational brochure on PTSD. The investigation led to a positive change in the practice environment and workflow of the clinic. We have not conducted any follow-up study as yet, but our goal is to screen all patients with mangled hand injury and refer all patients for psychiatric therapy who have positively answered 3 of the 4 screening questions.

Molecular phenotyping of a UK population: defining the human serum metabolome.

Phenotyping of 1,200 'healthy' adults from the UK has been performed through the investigation of diverse classes of hydrophilic and lipophilic metabolites present in serum by applying a series of chromatography-mass spectrometry platforms. These data were made robust to instrumental drift by numerical correction; this was prerequisite to allow detection of subtle metabolic differences. The variation in observed metabolite relative concentrations between the 1,200 subjects ranged from less than 5 % to more than 200 %. Variations in metabolites could be related to differences in gender, age, BMI, blood pressure, and smoking. Investigations suggest that a sample size of 600 subjects is both necessary and sufficient for robust analysis of these data. Overall, this is a large scale and non-targeted chromatographic MS-based metabolomics study, using samples from over 1,000 individuals, to provide a comprehensive measurement of their serum metabolomes. This work provides an important baseline or reference dataset for understanding the 'normal' relative concentrations and variation in the human serum metabolome. These may be related to our increasing knowledge of the human metabolic network map. Information on the Husermet study is available at http://www.husermet.org/. Importantly, all of the data are made freely available at MetaboLights (http://www.ebi.ac.uk/metabolights/).

Untargeted metabolic profiling identifies altered serum metabolites of type 2 diabetes mellitus in a prospective, nested case control study.

BACKGROUND: Application of metabolite profiling could expand the etiological knowledge of type 2 diabetes mellitus (T2D). However, few prospective studies apply broad untargeted metabolite profiling to reveal the comprehensive metabolic alterations preceding the onset of T2D. METHODS: We applied untargeted metabolite profiling in serum samples obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 300 individuals who developed T2D after a median follow-up time of 6 years and 300 matched controls. For that purpose, we used ultraperformance LC-MS with a protocol specifically designed for large-scale metabolomics studies with regard to robustness and repeatability. After multivariate classification to select metabolites with the strongest contribution to disease classification, we applied multivariable-adjusted conditional logistic regression to assess the association of these metabolites with T2D. RESULTS: Among several alterations in lipid metabolism, there was an inverse association with T2D for metabolites chemically annotated as lysophosphatidylcholine(dm16:0) and phosphatidylcholine(O-20:0/O-20:0). Hexose sugars were positively associated with T2D, whereas higher concentrations of a sugar alcohol and a deoxyhexose sugar reduced the odds of diabetes by approximately 60% and 70%, respectively. Furthermore, there was suggestive evidence for a positive association of the circulating purine nucleotide isopentenyladenosine-5'-monophosphate with incident T2D. CONCLUSIONS: This study constitutes one of the largest metabolite profiling approaches of T2D biomarkers in a prospective study population. The findings might help generate new hypotheses about diabetes etiology and develop further targeted studies of a smaller number of potentially important metabolites.

A metabolomic approach identifies differences in maternal serum in third trimester pregnancies that end in poor perinatal outcome.

Metabolomics offers a powerful holistic approach to examine the metabolite composition of biofluids to identify disruptions present in disease. We used ultra performance liquid chromatography-mass spectroscopy on the maternal serum obtained in the third trimester to address the hypothesis that pregnancies ending in poor outcomes (small for gestational age infant, preterm birth, or neonatal intensive care admission, n = 40) would have a different maternal serum metabolic profiles to matched healthy pregnancies (n = 40). Ninety-eight identified metabolic features differed between normal and poor pregnancy outcomes. Classes of metabolites perturbed included free fatty acids, glycerolipids, progesterone metabolites, sterol lipids, vitamin D metabolites, and sphingolipids; these highlight potential molecular mechanisms associated with pregnancy complications in the third trimester linked by placental dysfunction. In this clinical setting, metabolomics has the potential to describe differences in fetoplacental and maternal metabolites in pregnancies with poor pregnancy outcomes compared with controls.

Is serum or plasma more appropriate for intersubject comparisons in metabolomic studies? An assessment in patients with small-cell lung cancer.

In clinical analyses, the most appropriate biofluid should be analyzed for optimal assay performance. For biological fluids, the most readily accessible is blood, and metabolomic analyses can be performed either on plasma or serum. To determine the optimal agent for analysis, metabolic profiles of matched human serum and plasma were assessed by gas chromatography/time-of-flight mass spectrometry and ultrahigh-performance liquid chromatography mass spectrometry (in positive and negative electrospray ionization modes). Comparison of the two metabolomes, in terms of reproducibility, discriminative ability and coverage, indicated that they offered similar analytical opportunities. An analysis of the variation between 29 small-cell lung cancer (SCLC) patients revealed that the differences between individuals are markedly similar for the two biofluids. However, significant differences between the levels of some specific metabolites were identified, as were differences in the intersubject variability of some metabolite levels. Glycerophosphocholines, erythritol, creatinine, hexadecanoic acid, and glutamine in plasma, but not in serum, were shown to correlate with life expectancy for SCLC patients, indicating the utility of metabolomic analyses in clinical prognosis and the particular utility of plasma in relation to the clinical management of SCLC.

Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry.

Metabolism has an essential role in biological systems. Identification and quantitation of the compounds in the metabolome is defined as metabolic profiling, and it is applied to define metabolic changes related to genetic differences, environmental influences and disease or drug perturbations. Chromatography-mass spectrometry (MS) platforms are frequently used to provide the sensitive and reproducible detection of hundreds to thousands of metabolites in a single biofluid or tissue sample. Here we describe the experimental workflow for long-term and large-scale metabolomic studies involving thousands of human samples with data acquired for multiple analytical batches over many months and years. Protocols for serum- and plasma-based metabolic profiling applying gas chromatography-MS (GC-MS) and ultraperformance liquid chromatography-MS (UPLC-MS) are described. These include biofluid collection, sample preparation, data acquisition, data pre-processing and quality assurance. Methods for quality control-based robust LOESS signal correction to provide signal correction and integration of data from multiple analytical batches are also described.

Closed-loop, multiobjective optimization of analytical instrumentation: gas chromatography/time-of-flight mass spectrometry of the metabolomes of human serum and of yeast fermentations.

The number of instrumental parameters controlling modern analytical apparatus can be substantial, and varying them systematically to optimize a particular chromatographic separation, for example, is out of the question because of the astronomical number of combinations that are possible (i.e., the "search space" is very large). However, heuristic methods, such as those based on evolutionary computing, can be used to explore such search spaces efficiently. We here describe the implementation of an entirely automated (closed-loop) strategy for doing this and apply it to the optimization of gas chromatographic separations of the metabolomes of human serum and of yeast fermentation broths. Without human intervention, the Robot Chromatographer system (i) initializes the settings on the instrument, (ii) controls the analytical run, (iii) extracts the variables defining the analytical performance (specifically the number of peaks, signal/noise ratio, and run time), (iv) chooses (via the PESA-II multiobjective genetic algorithm), and (v) programs the next series of instrumental settings, the whole continuing in an iterative cycle until suitable sets of optimal conditions have been established. Genetic programming was used to remove noise peaks and to establish the basis for the improvements observed. The system showed that the number of peaks observable depended enormously on the conditions used and served to increase them by as much as 3-fold (e.g., to over 950 in human serum) while in many cases maintaining or reducing the run time and preserving excellent signal/noise ratios. The evolutionary closed-loop machine learning strategy we describe is generic to any type of analytical optimization.

Physical and psychosocial health in family caregiving: a comparison of AIDS and cancer caregivers.

The objectives of this study were to compare cancer and AIDS family caregivers in regard to their physical and emotional health. The sample consisted of 26 caregivers of persons with cancer or AIDS. Study participants completed a questionnaire that included measures of depression, grief, symptoms of stress, caregiving demands, interpersonal relationships, health status, and quality of life. The data revealed that both AIDS and cancer caregivers reported high levels of stress and depression as compared to community norms. No significant differences were found between AIDS and cancer caregivers for any of the scale scores; however, the two groups differed on several individual subscales. Cancer caregivers demonstrated higher social functioning and were more likely to report that the work of caregiving itself disrupted their ability to socially engage with others. In contrast, AIDS caregivers were more likely to report that their own health limited their ability to socialize. Even though AIDS caregivers experienced less family support than cancer caregivers, they reported more rewards from caregiving. Results suggest that support delivered to caregivers emphasize a more inclusive approach to program delivery, versus a disease-specific perspective, in order to increase the depth and breath of services provided to families undertaking these challenges.

Technology survey of nursing programs: implications for electronic end-of-life teaching tool development.

From an online survey of current technological capabilities of US undergraduate nursing programs, we found almost universal use of Microsoft Windows-based computers and Microsoft Office Suite software. Netscape and Microsoft Internet Explorer were the most popular browsers for Internet access. The survey also assessed faculty preferences for end-of-life care teaching materials and found that nurse educators preferred simple easy-to-use tools provided on CD-ROM or the Internet, with instructions provided via CD-ROM, the Internet, and demonstration workshops. Our findings have numerous implications for the development of electronic teaching materials for nursing.

Technology available in nursing programs: implications for developing virtual end-of-life educational tools.

BACKGROUND: To overcome insufficient attention to end-of-life (EOL) care in nursing education, the authors are developing the "Toolkit for Nursing Excellence at End-of-Life Transition" (TNEEL). METHOD: An evidence-based design process was used to create a computerized (CD-ROM) multimedia toolkit of instructional aides. An online survey of all U.S. undergraduate nursing programs was conducted to identify their current technologic infrastructures available for innovative teaching aides. Expert review process guided pedagogic decisions. RESULTS: Survey findings enabled TNEEL development to be responsive to nurse educators' needs and preferences. CONCLUSION: Educators can use TNEEL to actively engage students in meaningful learning about EOL care.